There is increasing evidence, throughout the nervous system, that homeostatic signaling systems, operating at the level of individual nerve and muscle cells, can interface with the mechanisms of neural plasticity to ensure that neural function remains stable over time. It is further hypothesized that defective homeostatic signaling could contribute to the cause or progression of diverse neurological disease. For example, maladaptive homeostatic signaling is hypothesized to participate in the progression of Alzheimer's Disease and post-traumatic epilepsy while impaired homeostatic signaling could reasonably contribute to other forms of epilepsy/channelopathy. Ultimately, clear links to neurological disease will require a detailed molecular understanding of homeostatic signaling in the nervous system. However, the molecular mechanisms responsible for the homeostatic regulation of neural function remain almost completely unknown. We have previously demonstrated that homeostatic signaling systems modulate neural function in Drosophila. In order to define the molecular mechanisms of homeostatic signaling, we have recently begun a forward genetic screen for mutations that block homeostatic signaling at the Drosophila neuromuscular junction (NMJ). Importantly, this screen uses synaptic electrophysiology as a direct, quantitative measure for altered neurotransmission. This screen has been highly successful. In this grant I present preliminary data for three newly identified genes that we have discovered are essential for synaptic homeostasis. Each of these genes is highly conserved and expressed throughout the vertebrate nervous system. These are among the very first genes to be implicated in the homeostatic modulation of presynaptic transmitter release in any organism. As such, our proposed experiments have the potential to significantly advance our understanding of how stable neural function is normally achieved, and how the stability of neural function becomes compromised during neurological disease. PUBLIC HEALTH RELEVANCE: Throughout the nervous system, there is now evidence that functional properties of neurons are controlled and stabilized by homeostatic signaling mechanisms. It is now widely hypothesized that defective homeostatic signaling could contribute to the cause or progression of diverse neurological diseases such as Alzheimer's Disease and epilepsy. We have recently identified three highly conserved genes that are required for the homeostatic modulation of neurotransmission and are among the very first genes implicated in this fundamental form neural regulation. Therefore, our proposed experiments have the potential to significantly advance our understanding of how stable neural function is normally achieved, and how the stability of neural function becomes compromised during neurological disease.